Halinchondrin analogs have been disclosed as having anticancer and antimitotic activity (U.S. Pat. No. 6,214,865, incorporated herein by reference). In particular, Halichondrin B has been reported as a potent anticancer agent that was first isolated from the marine sponge Halichondria okadai (U.S. Pat. No. 6,214,865; WO 2005/118565 A1 and WO 2009/124237 A1, all incorporated herein by reference). In addition, Eribulin, a Halichondrin B analog, has been reported as having potent anticancer properties (WO 2009/124237 A1, incorporated herein by reference).

The synthetic approach described (U.S. Pat. No. 6,214,865; WO 2009/124237 A1, Bioorg. Med. Chem. Lett., 2004, 14, 5551 and J. Am. Chem. Soc. 2009, 131, 15642, all incorporated herein by reference) involves introduction of nitrogen in the C27-C35 fragment of eribulin after assembly of the macrocycle. Such an approach can add synthetic steps to the later stages of the synthesis, after the building blocks corresponding to the C1-C13 and C14-C26 fragments have been introduced. The synthesis of those fragments is long and complex; and every additional step in the synthesis can imply an increase in manufacturing costs. In addition, due to the cytotoxic nature of eribulin, late introduction of the nitrogen results in a greater number of steps that can require special safety containment, which can limit throughput and can also increase the cost of producing the active pharmaceutical ingredient (API).
PCT publication numbers WO 2013/097042 and WO 2013/142999 (incorporated herein by reference) disclose process for preparation of the compound of formula 1, which corresponds to the C27-C35 fragment eribulin. The compound of formula 1 can help to mitigate a number of concerns associated with the manufacture of eribulin.

In the manufacture of eribulin, a number of the intermediates produced and used during the synthesis of eribulin can be present as liquid, making handling and storage challenging. Moreover, such liquid intermediates can require chromatographic purification that can make handling challenging and manufacturing at an industrial scale inefficient, expensive and undesirable.
There is a need in the art for solid intermediates that can be used in process for preparation of Halichondrin and its analogs, including eribulin. In addition, there is a need in the art for solid intermediates that can be purified by recrystallization, and are solid compounds under ambient conditions, which can assist in handling of such compounds or can help improve manufacturing efficiency. Moreover, there is a need in the art for a process for preparation of such intermediates.